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Dietary salt promotes cognitive impairment through tau phosphorylation

Giuseppe Faraco, Karin Hochrainer, Steven G. Segarra, Samantha Schaeffer, Monica M. Santisteban, Ajay Menon, Hong Jiang, David M. Holtzman, Josef Anrather, View ORCID ProfileCostantino Iadecola
doi: https://doi.org/10.1101/470666
Giuseppe Faraco
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
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Karin Hochrainer
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
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Steven G. Segarra
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
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Samantha Schaeffer
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
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Monica M. Santisteban
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
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Ajay Menon
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
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Hong Jiang
2Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO 63110
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David M. Holtzman
2Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO 63110
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Josef Anrather
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
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Costantino Iadecola
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
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  • ORCID record for Costantino Iadecola
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Abstract

Dietary habits and vascular risk factors promote both Alzheimer’s disease and cognitive impairment caused by vascular factors1-3. Furthermore, accumulation of hyperphosphorylated tau, a microtubule associated protein and a hallmark of Alzheimer’s pathology, is also linked to vascular cognitive impairment4-7. In mice, a salt-rich diet leads to cognitive dysfunction associated with a nitric oxide deficit in cerebral endothelial cells and cerebral hypoperfusion8. Here we report that dietary salt induces tau hyperphosphorylation followed by cognitive dysfunction, effects prevented by restoring endothelial nitric oxide production. The nitric oxide deficiency reduces neuronal calpain nitrosylation resulting in enzyme activation, which, in turn, leads to tau phosphorylation by activating cyclin dependent kinase-5. Salt-induced cognitive impairment is not observed in tau-null mice or in mice treated with anti-tau antibodies, despite persistent cerebral hypoperfusion and neurovascular dysfunction. These findings unveil a causal link between dietary salt, endothelial dysfunction and tau pathology, independent of hemodynamic insufficiency. Avoiding excessive salt intake and maintaining vascular health may help stave off vascular and neurodegenerative pathologies underlying late-life dementia.

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Posted November 14, 2018.
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Dietary salt promotes cognitive impairment through tau phosphorylation
Giuseppe Faraco, Karin Hochrainer, Steven G. Segarra, Samantha Schaeffer, Monica M. Santisteban, Ajay Menon, Hong Jiang, David M. Holtzman, Josef Anrather, Costantino Iadecola
bioRxiv 470666; doi: https://doi.org/10.1101/470666
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Dietary salt promotes cognitive impairment through tau phosphorylation
Giuseppe Faraco, Karin Hochrainer, Steven G. Segarra, Samantha Schaeffer, Monica M. Santisteban, Ajay Menon, Hong Jiang, David M. Holtzman, Josef Anrather, Costantino Iadecola
bioRxiv 470666; doi: https://doi.org/10.1101/470666

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